Abstract: Nuclear envelopathies encompass a variety of diseases, ranging from musculoskeletal disorders to neuronal defects. Amongst the most severe manifestations are progeria syndromes and Emery-Dreifuss dystrophies (EMD). Children affected with progeria syndromes suffer from grossly exacerbated aging symptoms and succumb to the disease in their mid-teens. EMD presents with muscle wasting, progressive loss of motility, heart failure and can lead to sudden death. Envelopathies are caused by mutations that affect proteins that reside in the nuclear envelope or the underlying lamina, a filamentous network that contributes to nuclear stability. Although the genetic basis for many of these diseases is established, the underlying mechanisms that lead to pathology remain poorly understood. The discovery of dominant alleles as genetic basis for many nuclear envelopathies, and the fact that several of those alleles do not display a phenotype upon genetic ablation in animal models, lead us to propose that these alleles act at least in part through proteotoxicity. Common to these diseases is the localization of the affected proteins to the nuclear envelope and lamina. The cellular mechanisms responsible for protein repair and turnover at these sites are largely unknown. Importantly, there is no known mechanism that accounts for turnover of protein aggregates in the nucleus, defining a major gap in our understanding of cellular protein quality control. At present, there are no suitable readouts available to assess whether proteotoxicity is in fact a contributing factor in the etiology of nuclear envelopathies. We propose to develop novel methodology that will allow us to scrutinize envelopathies from the perspective of protein quality control, and to identify the cellular mechanisms that safeguard protein quality control in the nuclear envelope and lamina. Moreover, we will exploit the conserved herpesvirus assembly machinery as unique handle to identify cellular factors implicated in regulating the dynamics of the nuclear envelope, and, specifically, transport of protein aggregates across the nuclear envelope. Collectively, our efforts will enable us to identify the pathways that are operative to safeguard protein homeostasis in the nuclear periphery. The results from our research endeavors have direct relevance for treatment of nuclear envelopathies and viral infections. Public Health Relevance: Pharmacological modulators of known components of the cellular protein quality control system are already in use for treatment of diseases as diverse as cystic fibrosis and cancer, or are in late stages of clinical trials. By delineating the quality control mechanisms in the nuclear periphery, we will add to the repertoire of drug targets, and facilitate the subsequent development of novel therapeutic strategies that can be used to treat nuclear envelopathies. In addition, the proposed activity will lead to the identification of cellular factors required for virus assembly, and thus define novel targets for therapeutic intervention, useful for the treatment of viral infections.